The aim of this proposal to examine and characterize the development of chronic kidney allograft rejection (chronic allograft nephropathy) and to study the effects of CD40-CD154 blockade on the development of this process. This topic has great clinical relevance for transplantation in general as chronic remains the major cause of renal allograft loss after the first year of transplantation. The applicant will utilize his background in the field of transplantation immunology and build o previous studies carried by the applicant and others. In particular the study will focus on the apparently discordant alloantigen dependent and independent factors that contribute to the process of chronic rejection and examine the role of the CD40-CD 154 pathway in this process. More specifically a new model of chronic renal allograft rejection in rats congenic for MHC will be set up and characterized. The advantages of this model are that it will provide a pure process of chronic rejection independent of the effects of immunosuppressive drugs. Having established the model the role of the CD40-CD 154 pathway will be examined in this model. This pathway has already been shown to be of critical importance in the development of acute rejection. This model can also be modified to test the effects o immunosuppressive drugs and how they modify the picture of clinical rejection and whether blockade of the CD40-CD154 pathway will be effected. Furthermore an established model of ischemia-reperfusion injury in the same host will be examined for the effects of CD40-CD 154 blockade in a setting where no alloantigen is present. Previous studies have indicated that prevention of T cell activation by blockade of the CD28-B7 pathway in this setting, can greatly ameliorate damage caused by ischemia-reperfusion injury. The processes involved in T cell activation in the absence of alloantigen are not well understood and examining the role CD40-CD154 pathway, ligation of which occurs earlier then the CD28-B7 costimulatory pathway will greatly help. These studies have broad implications to scientists working in area of chronic rejection. Understanding the mechanisms of how alloantigen dependent and independent pathways contribute to the overall process may provide novel therapeutic approaches for modulating the effects of chronic allograft rejection.